N-dealkylation of tertiary amines is a key chemical transformation in many processes for the preparation of clinically and commercially important compounds. Methods for N-dealkylation of tertiary amines are known in the art and include reaction of the tertiary amine with cyanogen bromide (see, e.g., U.S. Pat. No. 3,254,088; U.S. Pat. No. 3,433,791; and Cooley et al., “Amine Dealkylations with Acyl Chlorides” (1989) Synthesis 1-7), dialkyl azodicarboxylates including diethylazodicarboxylate and diisopropylazodicarboxylate, (see, e.g., GB 1,124,441), and haloformate reagents, including vinyl, methyl, ethyl, allyl, propyl, heptyl, phenyl, benzyl, α-chloro-ethyl, and 2,2,2-tri-chloro-ethyl chloroformates (see, e.g., U.S. Pat. Nos. 3,905,981 and 4,472,253; Olofson et al. (1984) J. Org. Chem. 49(11):2081-2083; and Rice et al. (1975) J. Org. Chem. 40(12):1850-1851).
Additional methods for N-dealkylation, particularly N-demethylation of tertiary amines, involve photochemical cleavage, as well as the formation and hydrolysis of dithiocarbamate, methyoxymethylether, and amine N-oxide intermediates to provide the corresponding secondary amine (“nor”) derivatives (see, e.g., Santamaria et al. (1989) Tetrahedron Lett. 30:2927; Santamaria et al. (1990) Tetrahedron Lett. 31:4735; Acosta et al. (1994) J. Chem. Soc., Chem. Commun. 17(7):1985-1986; Murahashi et al. (1988) J. Am. Chem. Soc. 110:8256; Murahashi (1995) Angew. Chem., Int. Ed., Engl. 34:2443; Polniaszek et al. (1992) J. Org. Chem. 57:4103; Murahashi et al. (1992) Tetrahedron Lett. 33:6991; Murahashi et al. (2003) J. Am. Chem. Soc. 125:15312; McCamley et al. (2003) J. Org. Chem. Soc. 68:9847; Gesson et al., “Preparation of N-Demethyl and N-Alkyl Analogs of L-Rhodosamine” (November 1990) Synlett. 669-670; Rosenau et al. (2004) Org. Lett. 6:541; Menchaca et al. (2003) J. Org. Chem. 68:8859; Periasamy et al. (2000) J. Org. Chem. 65:3548; Saaby et al. (2000) Angew. Chem., Int. Ed, Engl. 39:4114-4116; Denis et al. (2002) Tetrahedron Lett. 43:4171; and Zhang et al. (2005) Org. Lett. 7:3239).
As set forth in these references, the tertiary amine is converted to an intermediate that is subsequently cleaved to provide the corresponding dealkylated (e.g., demethylated) secondary amine. The secondary amine can then be realkylated, e.g., by condensation with an alkyl or alkenyl halide selected from among propyl iodide, cyclopropyl methyl bromide, cyclobutyl methyl bromide, and allyl bromide (see, e.g., U.S. Pat. Nos. 3,905,981; 4,141,897; 3,254,088; 3,332,950; and 3,433,791). The secondary amine can also be alkylated using reductive amination, involving reaction of the secondary amine with an alkyl aldehyde to provide an imine intermediate that can be reduced to a tertiary alkyl amine by hydrogenation in the presence of a transition metal catalyst. Alternatively, the secondary amine can be alkylated with an acid chloride to provide an amide intermediate that can be reduced to the corresponding tertiary alkyl amine, e.g., with diisobutylaluminum hydride (DIBALH).
These reactions, however, can involve the use of materials and reagents that are relatively expensive, toxic and environmentally burdensome. Such processes can also require purification of intermediates, extended process times, and harsh reaction conditions, and can provide overall yields that are not commercially viable.
For example, methods for the preparation of semi-synthetic opiate derivatives, e.g., naloxone, naltrexone, nalorphine, nalmefene, and nalbuphine, all involve removal of the naturally occurring opioid N-methyl group followed by replacement of that group with another alkyl or an alkenyl moiety. The ultimate starting materials for preparation of these semi-synthetic compounds include the natural products morphine, codeine, thebaine, and oripavine. Among these, thebaine and oripavine are particularly useful because they are readily oxidized to introduce the 14-hydroxy group carried by each of the above semi-synthetic opiates. In a similar manner, the semi-synthetic processes for the synthesis of buprenorphine, levallorphan, pentazocine, cyclazocine, and ketazocine also involve replacement of an N-methyl group of a tertiary amine with an alkyl or an alkenyl moiety.
N-demethylation of opiates with chloroformate reagents has been carried out in chlorinated solvents like 1,2-dichloroethane (DCE), chloroform (CHCl3) and dichloromethane (CH2Cl2). Where such solvents are employed in industrial scale commercial processes, the use of a halogenated solvent imposes additional process and environmental burdens, including, inter alia, the need for solvent exchanges where a protic solvent is required for hydrolysis of intermediates and products. In other instances, N-demethylation of opiates with chloroformate reagents has been carried out in acetonitrile. However, since acetonitrile is miscible in water, a solvent swap would be needed in order carry out aqueous washes of the reactions mixture after N-demethylation.
Accordingly, there remains a need for more efficient methods for the preparation of N-allyl derivatives of tertiary amines, as well as for improved processes incorporating those methods that would be robust, cost effective, amenable to commercial scale-up, and that would impose lower burdens on the environment. In particular, there remains a need for more efficient methods for the preparation of semi-synthetic opiate derivatives, including naloxone, naltrexone, nalmefene, nalbuphine, and buprenorphine, as well as levallorphan, pentazocine, cyclazocine, and ketazocine.